Systems analysis of the 22q11.2 microdeletion syndrome converges on a mitochondrial interactome necessary for synapse function and behavior

Avanti Gokhale, Cortnie Hartwig, Amanda A.H. Freeman, Julia L. Bassell, Stephanie A. Zlatic, Christie Sapp Savas, Trishna Vadlamudi, Farida Abudulai, Tyler T. Pham, Amanda Crocker, Erica Werner, Zhexing Wen, Gabriela M. Repetto, Joseph A. Gogos, Steven M. Claypool, Jennifer K. Forsyth, Carrie E. Bearden, Jill Glausier, David A. Lewis, Nicholas T. SeyfriedJennifer Q. Kwong, Victor Faundez

Research output: Contribution to journalArticle

Abstract

Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts from both sexes and mouse brains carrying a 22q11.2-like defect, Df(16)A+/-. Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A1 or SLC25A4 orthologues, dSLC25A1-sea and dSLC25A4-sesB, affected synapse morphology, neurotransmission, plasticity, and sleep patterns. Our findings indicate that synapses are sensitive to partial loss of function of mitochondrial solute transporters. We propose that mitoproteomes regulate synapse development and function in normal and pathological conditions in a cell-specific manner.

Original languageEnglish (US)
Pages (from-to)3561-3581
Number of pages21
JournalJournal of Neuroscience
Volume39
Issue number18
DOIs
StatePublished - May 1 2019

Keywords

  • 22q11.2 microdeletion
  • Mitochondria
  • SLC25A1
  • SLC25A4
  • Schizophrenia
  • Synapse

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Gokhale, A., Hartwig, C., Freeman, A. A. H., Bassell, J. L., Zlatic, S. A., Savas, C. S., Vadlamudi, T., Abudulai, F., Pham, T. T., Crocker, A., Werner, E., Wen, Z., Repetto, G. M., Gogos, J. A., Claypool, S. M., Forsyth, J. K., Bearden, C. E., Glausier, J., Lewis, D. A., ... Faundez, V. (2019). Systems analysis of the 22q11.2 microdeletion syndrome converges on a mitochondrial interactome necessary for synapse function and behavior. Journal of Neuroscience, 39(18), 3561-3581. https://doi.org/10.1523/JNEUROSCI.1983-18.2019